EP0077752B2 - Liquid mixture for absorbing and stabilizing gas bubbles to be used as contrast agent in ultrasonic diagnosis and process for its preparation - Google Patents
Liquid mixture for absorbing and stabilizing gas bubbles to be used as contrast agent in ultrasonic diagnosis and process for its preparation Download PDFInfo
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- EP0077752B2 EP0077752B2 EP82730129A EP82730129A EP0077752B2 EP 0077752 B2 EP0077752 B2 EP 0077752B2 EP 82730129 A EP82730129 A EP 82730129A EP 82730129 A EP82730129 A EP 82730129A EP 0077752 B2 EP0077752 B2 EP 0077752B2
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- 239000007788 liquid Substances 0.000 title claims abstract description 16
- 239000002872 contrast media Substances 0.000 title claims abstract description 7
- 239000000203 mixture Substances 0.000 title claims description 37
- 238000003745 diagnosis Methods 0.000 title claims description 3
- 238000000034 method Methods 0.000 title description 10
- 238000002360 preparation method Methods 0.000 title description 2
- 230000000087 stabilizing effect Effects 0.000 title 1
- 239000007789 gas Substances 0.000 claims description 31
- 239000000243 solution Substances 0.000 claims description 22
- 239000004094 surface-active agent Substances 0.000 claims description 17
- -1 polyoxyethylene Polymers 0.000 claims description 13
- 239000007864 aqueous solution Substances 0.000 claims description 11
- 229920001983 poloxamer Polymers 0.000 claims description 10
- 238000002604 ultrasonography Methods 0.000 claims description 10
- 239000000126 substance Substances 0.000 claims description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 9
- 229920000642 polymer Polymers 0.000 claims description 8
- 108010010803 Gelatin Chemical class 0.000 claims description 7
- 229920003171 Poly (ethylene oxide) Polymers 0.000 claims description 7
- 229920000159 gelatin Chemical class 0.000 claims description 7
- 239000008273 gelatin Chemical class 0.000 claims description 7
- 235000019322 gelatine Nutrition 0.000 claims description 7
- 235000011852 gelatine desserts Nutrition 0.000 claims description 7
- 229920002503 polyoxyethylene-polyoxypropylene Polymers 0.000 claims description 7
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 claims description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 4
- 235000014113 dietary fatty acids Nutrition 0.000 claims description 4
- 239000000194 fatty acid Substances 0.000 claims description 4
- 229930195729 fatty acid Natural products 0.000 claims description 4
- 239000000787 lecithin Substances 0.000 claims description 4
- 235000010445 lecithin Nutrition 0.000 claims description 4
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 3
- 239000001569 carbon dioxide Substances 0.000 claims description 3
- 229910002092 carbon dioxide Inorganic materials 0.000 claims description 3
- 229910052760 oxygen Inorganic materials 0.000 claims description 3
- 239000001301 oxygen Substances 0.000 claims description 3
- 108010014241 oxypolygelatine Chemical class 0.000 claims description 3
- 230000006641 stabilisation Effects 0.000 claims description 3
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 claims description 2
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical class O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 claims description 2
- 108010017384 Blood Proteins Chemical class 0.000 claims description 2
- 102000004506 Blood Proteins Human genes 0.000 claims description 2
- 229920000858 Cyclodextrin Chemical class 0.000 claims description 2
- 229920002307 Dextran Chemical class 0.000 claims description 2
- 229920001612 Hydroxyethyl starch Chemical class 0.000 claims description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 claims description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical class O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 claims description 2
- 229930006000 Sucrose Chemical class 0.000 claims description 2
- 239000004359 castor oil Substances 0.000 claims description 2
- 229940097362 cyclodextrins Drugs 0.000 claims description 2
- 239000008151 electrolyte solution Substances 0.000 claims description 2
- 150000004676 glycans Chemical class 0.000 claims description 2
- 229940050526 hydroxyethylstarch Drugs 0.000 claims description 2
- 239000003978 infusion fluid Substances 0.000 claims description 2
- 239000008101 lactose Substances 0.000 claims description 2
- 229940067606 lecithin Drugs 0.000 claims description 2
- 229910052757 nitrogen Inorganic materials 0.000 claims description 2
- 229910052756 noble gas Inorganic materials 0.000 claims description 2
- 239000002736 nonionic surfactant Substances 0.000 claims description 2
- 229920001282 polysaccharide Chemical class 0.000 claims description 2
- 239000005017 polysaccharide Chemical class 0.000 claims description 2
- 238000011105 stabilization Methods 0.000 claims description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims 1
- 239000003570 air Substances 0.000 claims 1
- 235000013681 dietary sucrose Nutrition 0.000 claims 1
- 229960004793 sucrose Drugs 0.000 claims 1
- 238000013019 agitation Methods 0.000 abstract 1
- 150000001875 compounds Chemical class 0.000 abstract 1
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 8
- 239000007924 injection Substances 0.000 description 6
- 238000002347 injection Methods 0.000 description 6
- 238000004519 manufacturing process Methods 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 5
- 238000002156 mixing Methods 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- 229910052786 argon Inorganic materials 0.000 description 4
- 210000002216 heart Anatomy 0.000 description 4
- 235000002639 sodium chloride Nutrition 0.000 description 4
- 239000011780 sodium chloride Substances 0.000 description 4
- 239000012298 atmosphere Substances 0.000 description 3
- 239000008280 blood Substances 0.000 description 3
- 210000004369 blood Anatomy 0.000 description 3
- 229940119744 dextran 40 Drugs 0.000 description 3
- 238000009826 distribution Methods 0.000 description 3
- 238000002592 echocardiography Methods 0.000 description 3
- FZWBNHMXJMCXLU-BLAUPYHCSA-N isomaltotriose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1OC[C@@H]1[C@@H](O)[C@H](O)[C@@H](O)[C@@H](OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C=O)O1 FZWBNHMXJMCXLU-BLAUPYHCSA-N 0.000 description 3
- 241000282472 Canis lupus familiaris Species 0.000 description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- 239000001307 helium Substances 0.000 description 2
- 229910052734 helium Inorganic materials 0.000 description 2
- SWQJXJOGLNCZEY-UHFFFAOYSA-N helium atom Chemical compound [He] SWQJXJOGLNCZEY-UHFFFAOYSA-N 0.000 description 2
- 210000005240 left ventricle Anatomy 0.000 description 2
- 239000002504 physiological saline solution Substances 0.000 description 2
- 230000001954 sterilising effect Effects 0.000 description 2
- 206010002198 Anaphylactic reaction Diseases 0.000 description 1
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 1
- 208000019693 Lung disease Diseases 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000036783 anaphylactic response Effects 0.000 description 1
- 208000003455 anaphylaxis Diseases 0.000 description 1
- 239000012300 argon atmosphere Substances 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 239000001110 calcium chloride Substances 0.000 description 1
- 229910001628 calcium chloride Inorganic materials 0.000 description 1
- 235000011148 calcium chloride Nutrition 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 210000000038 chest Anatomy 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000007435 diagnostic evaluation Methods 0.000 description 1
- 239000002961 echo contrast media Substances 0.000 description 1
- 229940021013 electrolyte solution Drugs 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 238000003384 imaging method Methods 0.000 description 1
- 229960004657 indocyanine green Drugs 0.000 description 1
- MOFVSTNWEDAEEK-UHFFFAOYSA-M indocyanine green Chemical compound [Na+].[O-]S(=O)(=O)CCCCN1C2=CC=C3C=CC=CC3=C2C(C)(C)C1=CC=CC=CC=CC1=[N+](CCCCS([O-])(=O)=O)C2=CC=C(C=CC=C3)C3=C2C1(C)C MOFVSTNWEDAEEK-UHFFFAOYSA-M 0.000 description 1
- 230000036512 infertility Effects 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 239000006193 liquid solution Substances 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 238000010907 mechanical stirring Methods 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 150000002835 noble gases Chemical class 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 208000002815 pulmonary hypertension Diseases 0.000 description 1
- 239000002510 pyrogen Substances 0.000 description 1
- 210000005241 right ventricle Anatomy 0.000 description 1
- HELHAJAZNSDZJO-OLXYHTOASA-L sodium L-tartrate Chemical compound [Na+].[Na+].[O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O HELHAJAZNSDZJO-OLXYHTOASA-L 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 235000011083 sodium citrates Nutrition 0.000 description 1
- 239000001433 sodium tartrate Substances 0.000 description 1
- 229960002167 sodium tartrate Drugs 0.000 description 1
- 235000011004 sodium tartrates Nutrition 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000005507 spraying Methods 0.000 description 1
- 238000011146 sterile filtration Methods 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 239000005720 sucrose Chemical class 0.000 description 1
- 238000012800 visualization Methods 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/22—Echographic preparations; Ultrasound imaging preparations ; Optoacoustic imaging preparations
- A61K49/222—Echographic preparations; Ultrasound imaging preparations ; Optoacoustic imaging preparations characterised by a special physical form, e.g. emulsions, liposomes
- A61K49/223—Microbubbles, hollow microspheres, free gas bubbles, gas microspheres
Definitions
- the invention relates to a liquid composition for the absorption and stabilization of gas bottles filled with physiologically compatible gas for use as a contrast agent for the ultrasound diagnosis of liquid-filled vessels or cavities of the human and animal body.
- US Pat. No. 4,265,251 describes the production of micro-gas bubbles with a saccharide shell, which can be produced using a complex, complex apparatus with a reproducible size distribution.
- the disadvantages of this method lie in the fact that the micro-bubbles are openly mixed with the carrier shortly before use, as a result of which sterility and freedom from pyrogens are not guaranteed. On the other hand, the production is expensive due to the complex technology.
- Patent 4,276,885
- Carroll Barbara A., et al. in Invest. Radiol. 1980. 15 (3).
- 260-266 describes a process for producing micro-gas bubbles with a gelatin membrane and using a gellable medium as a carrier for these micro-bubbles so that the gas bubbles can be frozen by cooling and, if necessary, released again by heating.
- a disadvantage of this method is the fact that a suspension produced in this way cannot be sterilized, since the microbubbles are not stable and can also be stored by heat sterilization Sterile filtration is separated or destroyed. In addition, gelatin preparations always present a risk of anaphylaxis.
- the invention relates to a liquid composition according to claim 1.
- the two liquid mixtures can be mixed by any method by which vigorous turbulence is achieved, for example by mechanical stirring or by ultrasound or by drawing up one Mixing in an injection syringe and emptying this syringe into the second mixture using the highest possible pressure and high outflow speed and subsequent vigorous shaking, sterile conditions must be ensured for all mixing processes.
- a vessel is used for the mixing process which enables sterile conditions and is large enough and, after the second mixture has been taken up, has a sufficiently large gas space for the subsequent vigorous shaking.
- Sufficiently large multivials with a closure, which can be pierced with an injection needle, are preferably used for this, thus allowing the mixture to be injected, subsequently mixed and the liquid mixture provided with bubbles to be removed without opening.
- the bubbles are familiar with other physiologically compatible sterile gases such as carbon dioxide. Oxygen, nitrogen, noble gases or filled with their mixtures, being sterile air. Carbon dioxide and or oxygen are preferred.
- the air is displaced from the mixture of the surfactant or surfactant mixture and or from the mixture of the viscosity-increasing substance by gassing with the desired gas and both mixtures are mixed in one of the ways described above in a multivial which is filled with the desired gas or gas mixture .
- the mixtures are prepared for intravenous administration as a contrast medium for ultrasound diagnostics.
- a contrast medium is therefore available for ultrasound diagnostics that is free of solid particles and is sterile.
- the surfactants are non-ionic surfactants from the group: lecithins, lecithin fractions and their modification products, polyoxyethylene fatty acid esters, polyoxyethylene fatty alcohol ethers, ethoxylated castor oils and their hydrogenated derivatives, polyoxyethylene polyoxypropylene polymers, whereby polyoxyethylene fatty acid stearates and polyoxyethylene 800 and 300 molyoxypropylene polymers 250 are preferred. All percentages refer to percentages by weight.
- the contrast medium solution contains at least 0.01% of a surfactant or a mixture of several surfactants, the preferred content being 0.5 to 5% of surfactant or surfactant mixture.
- the viscosity-increasing substances are polysaccharides, lactose, sucrose, dextrans, cyclodextrins, hydroxyethyl starch, plasma proteins, gelatin, oxypolygelatin and gelatin derivatives or their mixtures, and polyoxyethylene polyoxypropylene polymers with a molecular weight of 4,750-16,250.
- the concentration of these substances mentioned in the solution is at least 0.5%, the maximum concentration also depending on the solute.
- gelatin with a concentration of 0.5 to 2% can be used.
- the oxypolygelatin is preferably used in a concentration of 0.5 to 10%.
- surfactants which have a viscosity-increasing action at the same time as polyoxyethylene-polyoxypropylene polymers with a molecular weight of 4,750 to 16,250.
- concentration of the surfactants with a viscosity-increasing action in the total solution is 1% to 10%, preferably 3% to 10% .
- the surfactant or surfactant mixture is preferably dissolved in water or a physiologically tolerated aqueous solution in the presence of the viscosity-increasing substance or mixture of substances.
- physiological electrolyte solutions such as physiological saline, Ringer's solution or the aqueous solutions of sodium chloride, calcium chloride, sodium hydrogen carbonate, sodium citrate, sodium acetate or Sodium tartrate or saline solutions (infusion solutions) can be used.
- a vesicle suspension for ultrasound contrast imaging of the right ventricle of the heart in dogs (beagle dogs of 17.2 kg body weight, 2.5 years old, male, closed thorax), 0.3 ml of a vesicle suspension is used, which is sterilized by vigorous swirling of 2 ml of 5% aqueous solution Pluronic (R) 68 solution and 8 ml aqueous sterilized 5% glucose solution was generated in a sterile air atmosphere.
- Pluronic (R) F 68 solution was drawn up with an injection syringe, this solution was injected into a multivial with the glucose solution at a high outflow rate and then shaken.
- the size distribution of the gas bubbles was determined 2 minutes after production using a Cilas granulometer 715 and was 35 ⁇ m for 50% of the gas bubbles.
- the visualization and recording of the ultrasound echoes and their diagnostic evaluation takes place in a manner known per se and is described, for example, in USP 4,276,885 and by HL Wyatt et al. in Circulation 60, p. 1 104 f (1979).
- a 10% aqueous and sterile Pluronic (R) F 127 solution is removed with an injection syringe and injected with the highest possible outflow rate in 8 ml of a sterile physiological saline solution, which is in a sterile 25 ml multivial under an air atmosphere. The mixture is then shaken vigorously.
- the gas bubble suspension contains 2% Pluronic (R) F 127 and 0.9% table salt.
- the average bubble size determined with a modified Cilas granulometer 2 minutes after production is ⁇ 45 ⁇ m for 50%.
- Example 2 Analogously to Example 2, but using helium instead of argon, a helium gas bubble suspension is obtained after the mixing process, which contains 1% Pluronic (R) F 68 and 4.8% dextran 40.
Abstract
Description
Die Erfindung betrifft eine flüssige Zusammensetzung zur Aufnahme und Stabilisierung von mit physiologisch verträglichem Gas gefüllten Gasblaschen zur Verwendung als Kontrastmittel für die Ultraschalldiagnostik von mit Flüssigkeit gefüllten Gefäßen oder Hohlräumen des menschlichen und tierischen Körpers.The invention relates to a liquid composition for the absorption and stabilization of gas bottles filled with physiologically compatible gas for use as a contrast agent for the ultrasound diagnosis of liquid-filled vessels or cavities of the human and animal body.
Es ist allgemein bekannt, daß der Kontrast in der Ultraschall-Diagnostik durch die Anwesenheit von Gasbläschen in der Flüssigkeit (Blut), die das Untersuchungsobjekt durchströmt, erhöht wird. Zu diesem Zweck kann man diese Gas-Bläschen außerhalb des Untersuchungsobjektes herstellen und in den Blutstrom injizieren. Beispielsweise ist dies möglich, indem man eine flüssige Lösung wie Kochsalzlösung, eine Farbstofflösung (Ziskin, Marvin C. et al., Invest. Radiol. 1972. 7-6. 500-505) oder vorher entnommenes Blut heftig schüttelt, um die Bläschen zu erzeugen, danach injiziert und die Ultraschall-Untersuchung durchführt. So berichtet Feigenbaum et al., in dem Artikel 〈〈 Identification of Ultrasound Echoes From the Left Ventricle of the Heart Through the Use of Injections of Indocyanine Green 〉〉 (Circulation, Volume XLI. April 1970) über die Erzeugung von Echos durch Gasbläschen im linken Ventrikel des Herzens, ähnlich wie auch von Gramiak et al. (Radiology 100. 415-418. 1971) berichtet wird. Ein anderes Verfahren zur Erzeugung von Mikro-Gasbläschen mit bestimmter Größe wird in dem Bericht 〈〈 Non-Invasive Assessment of Pulmonary Hypertension Using The Bubble Ultrasonic Resonance Pressure (BURP) Method 〉〉 (Report No. HR-62917-1A. Apr. 1977. Division of Lung Diseases, National Heart, Lung and Blood Institute) beschrieben.It is generally known that the contrast in ultrasound diagnostics is increased by the presence of gas bubbles in the liquid (blood) which flows through the object under examination. For this purpose, these gas bubbles can be produced outside the object to be examined and injected into the bloodstream. For example, this is possible by vigorously shaking a liquid solution such as saline, a dye solution (Ziskin, Marvin C. et al., Invest. Radiol. 1972. 7-6. 500-505) or previously drawn blood to close the vesicles generate, then injected and performed the ultrasound examination. Feigenbaum et al., In the article 〈〈 Identification of Ultrasound Echoes From the Left Ventricle of the Heart Through the Use of Injections of Indocyanine Green 〉〉 (Circulation, Volume XLI. April 1970) reports on the generation of echoes by gas bubbles in the left ventricle of the heart, similar to that of Gramiak et al. (Radiology 100, 415-418. 1971). Another method for producing micro gas bubbles of a certain size is described in the report 〈〈 Non-Invasive Assessment of Pulmonary Hypertension Using The Bubble Ultrasonic Resonance Pressure (BURP) Method 〉〉 (Report No. HR-62917-1A. Apr. 1977 Division of Lung Diseases, National Heart, Lung and Blood Institute).
In dem US-Patent Nr. 4 265 251 wird die Herstellung von mikro-Gasbläschen mit einer Saccharid-Hülle beschrieben, die durch die Verwendung einer aufwendigen komplizierten Apparatur mit reproduzierbarer Größenverteilung hergestellt werden können. Die Nachteile dieses Verfahrens liegen einmal darin, daß die mikro-Bläschen kurz vor der Verwendung mit dem Träger offen durchgemischt werden, wodurch Sterilität und Pyrogenfreiheit nicht gewährleistet sind. Zum anderen verursacht,die Herstellung durch die aufwendige Technik hohe Kosten. In einem weiteren US-Patent (4 276 885) und von Carroll. Barbara A., et al. in Invest. Radiol. 1980. 15 (3). 260-266 wird beispielsweise ein Verfahren beschrieben, mikro-Gasbläschen mit einer Gelatinemembrane herzustellen und als Träger für diese Mikro-Bläschen ein gelierbares Medium zu verwenden, damit die Gasbläschen durch Abkühlen eingefroren und bei Bedarf durch Erwärmen wieder in Freiheit gesetzt werden können.US Pat. No. 4,265,251 describes the production of micro-gas bubbles with a saccharide shell, which can be produced using a complex, complex apparatus with a reproducible size distribution. The disadvantages of this method lie in the fact that the micro-bubbles are openly mixed with the carrier shortly before use, as a result of which sterility and freedom from pyrogens are not guaranteed. On the other hand, the production is expensive due to the complex technology. In another U.S. Patent (4,276,885) and Carroll. Barbara A., et al. in Invest. Radiol. 1980. 15 (3). For example, 260-266 describes a process for producing micro-gas bubbles with a gelatin membrane and using a gellable medium as a carrier for these micro-bubbles so that the gas bubbles can be frozen by cooling and, if necessary, released again by heating.
Nachteilig bei dieser Methode ist die Tatsache, daß eine so erzeugte Suspension nicht sterilisiert werden kann, da bei Hitzesterilisation die Mikro-Bläschen nicht haltbar sind und auch durch Sterilfiltration abgetrennt oder zerstört werde Dazu kommt, daß Gelatinezubereitungen stets ein Anaphylaxie-Risiko darsteilen.A disadvantage of this method is the fact that a suspension produced in this way cannot be sterilized, since the microbubbles are not stable and can also be stored by heat sterilization Sterile filtration is separated or destroyed. In addition, gelatin preparations always present a risk of anaphylaxis.
Durch die Bereitstellung des erfindungsgemäßen neuen Ultraschall-Kontrastmitels werden die geschilderten Nachteile beseitigt. Gegenstand der Erfindung ist eine flüssige Zusammensetzung gemäß Anspruch 1.The disadvantages described are eliminated by the provision of the new ultrasound contrast medium according to the invention. The invention relates to a liquid composition according to claim 1.
Die Herstellung der Bläschen kurz vor der Verwendung kann auf die verschiedenste Weise erfolgen:
- 1. Durch Mitaufziehen von Luft oder physiologisch verträglichem Gas beim Aufziehen der erfindungsgemäßen Mischung und mehrmaliger Wiederholung von Aufziehen und Ausspritzen sog. Pumpen) unter sterilen Bedingungen.
- 2. Durch zunächst getrenntes Herstellen und nachfolgende Hitzesterilisation der Mischung von Tensid in Wasser oder einer physiologisch verträglichen wäßrigen Lösung und der Mischung des viskositätserhöhenden Stoffes in Wasser oder einer physiologisch verträglichen wäßrigen Losung. Aufziehen der ersten Mischung und nachfolgendes Einspritzen dieser ersten Mischung in die zweite, die sich in einem steilen Gefäß zusammen mit einem physiologisch verträglichen Gas befindet.
- 3. Durch Aufbewahrung einer sterilen Mischung von Tensid und viskositätserhöhenden Stoff in Wasser oder einer physiologisch verträglichen wäßrigen Lösung in einer sterilen Atmosphäre eines physiologisch verträglichen Gases unter einem Druck, der größer als der Normaldruck ist, vorzugsweise in einem druckfest verschließbaren Gefäß mit einer Vorrichtung zum Ablassen des Überdrucks, indem man, gegebenenfalls nach vorherigem Schütteln zum besseren Vermischen des Gases mit der Lösung, den Überdruck entweichen läßt.
- 1. By drawing in air or physiologically compatible gas when drawing up the mixture according to the invention and repeating drawing and spraying out several times (so-called pumps) under sterile conditions.
- 2. By separately preparing and then heat sterilizing the mixture of surfactant in water or a physiologically compatible aqueous solution and the mixture of the viscosity-increasing substance in water or a physiologically compatible aqueous solution. Draw up the first mixture and then inject this first mixture into the second, which is in a steep vessel together with a physiologically compatible gas.
- 3. By storing a sterile mixture of surfactant and viscosity-increasing substance in water or a physiologically compatible aqueous solution in a sterile atmosphere of a physiologically compatible gas under a pressure which is greater than normal pressure, preferably in a pressure-tight sealable vessel with a device for draining off the excess pressure by letting the excess pressure escape, if necessary after shaking beforehand, for better mixing of the gas with the solution.
Das Vermischen der beiden flüssigen Mischungen kann mit jeder Methode erfolgen, durch die eine kräftige Verwirbelung erzielt wird, beispielsweise durch mechanisches Rühren oder durch Ultraschall oder durch Aufziehen der einen Mischung in eine Injektionsspritze und Entleeren dieser Spritze in die zweite Mischung unter Anwendung von möglichst hohem Druck und hoher Ausströmungsgeschwindigkeit und nachfolgendes kräftiges Schütteln, wobei für alle Mischungsvorgänge sterile Bedingungen gewährleistet sein müssen. Beispielsweise wird für den Mischvorgang ein Gefäß verwendet, das sterile Bedingungen ermöglicht und groß genug ist und nach der Aufnahme der zweiten Mischung für das nachfolgende kräftige Schütteln noch einen genügend großen Gasraum besitzt. Vorzugsweise verwendet man dafür genügend große Multivials mit einem Verschluß, der mit einer Injektionsnadel durchstochen werden kann und so das Einspritzen der Mischung, das nachfolgende Durchmischen und die Entnahme der mit Bläschen versehenen flüssigen Mischung ohne Öffnen erlaubt.The two liquid mixtures can be mixed by any method by which vigorous turbulence is achieved, for example by mechanical stirring or by ultrasound or by drawing up one Mixing in an injection syringe and emptying this syringe into the second mixture using the highest possible pressure and high outflow speed and subsequent vigorous shaking, sterile conditions must be ensured for all mixing processes. For example, a vessel is used for the mixing process which enables sterile conditions and is large enough and, after the second mixture has been taken up, has a sufficiently large gas space for the subsequent vigorous shaking. Sufficiently large multivials with a closure, which can be pierced with an injection needle, are preferably used for this, thus allowing the mixture to be injected, subsequently mixed and the liquid mixture provided with bubbles to be removed without opening.
Falls erforderlich, kennen die Bläschen anstelle mit steriler Luft mit anderen physiologisch verträglichen sterilen Gasen wie beispielsweise Kohlendioxid. Sauersoff, Stickstoff, Edelgasen oder mit deren Gemischen gefüllt sein, wobei sterile Luft. Kohlendioxid und oder Sauerstoff bevorzugt sind. Zu diesem Zweck wird aus der Mischung des Tensides oder Tensidgemisches und oder aus der Mischung der viskositatserhöhenden Substanz durch Begasung mit dem gewünschten Gas die Luft verdrängt und beide Mischungen in einer der vorbeschriebenen Weisen in einem Multivial gemischt, das mit dem gewünschten Gas oder Gasgemisch gefüllt ist.If necessary, instead of using sterile air, the bubbles are familiar with other physiologically compatible sterile gases such as carbon dioxide. Oxygen, nitrogen, noble gases or filled with their mixtures, being sterile air. Carbon dioxide and or oxygen are preferred. For this purpose, the air is displaced from the mixture of the surfactant or surfactant mixture and or from the mixture of the viscosity-increasing substance by gassing with the desired gas and both mixtures are mixed in one of the ways described above in a multivial which is filled with the desired gas or gas mixture .
Nach der Erzeugung der Bläschen in einer der angegebenen oder äquivalenten Verfahrensweise sind die Mischungen zur intravenösen Verabreichung als Kontrastmittel für die Ultraschalldiagnostik vorbereitet.After the vesicles have been generated in one of the specified or equivalent procedures, the mixtures are prepared for intravenous administration as a contrast medium for ultrasound diagnostics.
Es steht damit ein Kontrastmittel für die Ultraschalldiagnostik zur Verfügung, das frei ist von festen Partikeln und steril ist.A contrast medium is therefore available for ultrasound diagnostics that is free of solid particles and is sterile.
Die Tenside sind nichtionogene Tenside aus der Gruppe: Lecithine, Lecithinfraktionen und deren Abwandlungsprodukte, Polyoxyethylenfettsäureester, Polyoxyethylenfettalkoholäther, ethoxylierte Rizinusöle und deren hydrierte Derivate, Polyoxyethylenpolyoxypropylen-Polymere, wobei Polyoxyäthylenfettsäurestearate und Polyoxyethylenpolyoxypropylen-Polymere mit dem Molgewicht 6 800-8 975. 13 300 und 16 250 bevorzugt sind. Sämtliche Prozentangaben beziehen sich auf Gewichtsprozente.The surfactants are non-ionic surfactants from the group: lecithins, lecithin fractions and their modification products, polyoxyethylene fatty acid esters, polyoxyethylene fatty alcohol ethers, ethoxylated castor oils and their hydrogenated derivatives, polyoxyethylene polyoxypropylene polymers, whereby polyoxyethylene fatty acid stearates and polyoxyethylene 800 and 300 molyoxypropylene polymers 250 are preferred. All percentages refer to percentages by weight.
Die Kontrastmittel-Lösung enthält erfindungsgemäß mindestens 0,01% eines Tensides oder des Gemisches mehrerer Tenside, wobei der bevorzugte Gehalt 0,5 bis 5% Tensid oder Tensidgemisch beträgt.According to the invention, the contrast medium solution contains at least 0.01% of a surfactant or a mixture of several surfactants, the preferred content being 0.5 to 5% of surfactant or surfactant mixture.
Die viskositätserhöhenden Substanzen sind Polysaccharide, Lactose, Saccharose, Dextrane, Cyclodextrine, Hydroxyäthylstärke, Plasmaproteine, Gelatine, Oxypolygelatine und Gelatine derivate oder deren Gemische sowie Polyoxyethylenpolyoxypropylen-Polymere mit einem Molekulargewicht von 4 750-16 250.The viscosity-increasing substances are polysaccharides, lactose, sucrose, dextrans, cyclodextrins, hydroxyethyl starch, plasma proteins, gelatin, oxypolygelatin and gelatin derivatives or their mixtures, and polyoxyethylene polyoxypropylene polymers with a molecular weight of 4,750-16,250.
Die Konzentration dieser genannten Stoffe in der Lösung beträgt erfindungsgemäß mindestens 0,5%, wobei die Höchstkonzentration auch vom gelösten Stoff abhängt. So kann beispielsweise Gelatine mit einer Konzentration von 0,5 bis 2% verwendet werden. Die Oxypolygelatine wird bevorzugt mit einer Konzentration von 0,5 bis 10% eingesetzt.According to the invention, the concentration of these substances mentioned in the solution is at least 0.5%, the maximum concentration also depending on the solute. For example, gelatin with a concentration of 0.5 to 2% can be used. The oxypolygelatin is preferably used in a concentration of 0.5 to 10%.
Man kann auch Tenside verwenden, die gleichzeitig viskositätserhöhend wirken wie Polyoxyethylenpolyoxypropylen-Polymere mit dem Molekulargewicht von 4 750 bis 16 250. In diesem Fall beträgt die Konzentration der Tenside mit viskositätserhöhender Wirkung in der Gesamtlösung 1% bis 10%, vorzugsweise 3% bis 10%. Das Tensid oder Tensidgemisch wird vorzugsweise in Gegenwart des viskositätserhöhenden Stoffes oder Stoffgemisches in Wasser oder einer physiologisch verträglichen wäßrigen Lösung gelöst. Als physiologisch verträgliche wäßrige Lösung können beispielsweise physiologische Elektrolytlösungen wie physiologische Kochsalzlösung, Ringerlösung oder die wäßrigen Lösungen von Natriumchlorid, Kalziumchlorid, Natriumhydrogencarbonat, Natriumcitrat, Natriumazetat oder Natriumtartrat oder Salzlösungen (Infusionslösungen) verwendet werden.It is also possible to use surfactants which have a viscosity-increasing action at the same time as polyoxyethylene-polyoxypropylene polymers with a molecular weight of 4,750 to 16,250. In this case, the concentration of the surfactants with a viscosity-increasing action in the total solution is 1% to 10%, preferably 3% to 10% . The surfactant or surfactant mixture is preferably dissolved in water or a physiologically tolerated aqueous solution in the presence of the viscosity-increasing substance or mixture of substances. As a physiologically compatible aqueous solution, for example, physiological electrolyte solutions such as physiological saline, Ringer's solution or the aqueous solutions of sodium chloride, calcium chloride, sodium hydrogen carbonate, sodium citrate, sodium acetate or Sodium tartrate or saline solutions (infusion solutions) can be used.
So werden beispielsweise für die Ultraschall-Kontrastaufnahme der rechten Herzkammer beim Hund (Beagle Hunde von 17.2 kg Körpergewicht, 2.5 Jahre alt, männlich, geschlossener Thorax) 0.3 ml einer Bläschen-Suspension verwendet, die durch starkes Verwirbeln von 2 ml 5 %iger wäßriger sterilisierter Pluronic (R) 68-Lösung und 8 ml wäßriger sterilisierter 5 %iger Glucose-Lösung in einer sterilen Luftatmosphäre erzeugt wurde. Zur Verwirbelung wurde die Pluronic(R) F 68-Lösung mit einer Injektionsspritze aufgezogen, diese Lösung in ein Multivial mit der Glucoselösung mit hoher Ausströmungsgeschwindigkeit gespritzt und anschließend geschüttelt. Die Größenverteilung der Gasbläschen wurde 2 Minuten nach der Herstellung mit einem Cilas-Granulometer 715 bestimmt und betrug für 50 % der Gasbläschen 35 µm. Die Sichtbarmachung und Aufzeichnung der Ultraschall-Echos sowie deren diagnostische Auswertung erfolgt in an sich bekannter Weise und ist zum Beispiel in USP 4 276 885 sowie von H. L. Wyatt et al. in Circulation 60. S. 1 104 f (1979) beschrieben.For example, for ultrasound contrast imaging of the right ventricle of the heart in dogs (beagle dogs of 17.2 kg body weight, 2.5 years old, male, closed thorax), 0.3 ml of a vesicle suspension is used, which is sterilized by vigorous swirling of 2 ml of 5% aqueous solution Pluronic (R) 68 solution and 8 ml aqueous sterilized 5% glucose solution was generated in a sterile air atmosphere. For swirling, the Pluronic (R) F 68 solution was drawn up with an injection syringe, this solution was injected into a multivial with the glucose solution at a high outflow rate and then shaken. The size distribution of the gas bubbles was determined 2 minutes after production using a Cilas granulometer 715 and was 35 μm for 50% of the gas bubbles. The visualization and recording of the ultrasound echoes and their diagnostic evaluation takes place in a manner known per se and is described, for example, in USP 4,276,885 and by HL Wyatt et al. in Circulation 60, p. 1 104 f (1979).
Einer 10 %igen wäßrigen und sterilen Pluronic (R) F 127-Lösung werden 2 ml mit einer Injektionsspritze entnommen und mit möglichst hoher Ausströmungsgeschwindigkeit in 8 ml einer sterilen physiologischen Kochsalzlösung, die sich in einem sterilen 25 ml Multivial unter einer Luftatmosphäre befinden, gespritzt. Anschließend wird die Mischung stark geschüttelt. Die hergestellte Gasblasensuspension enthalt 2 % Pluronic (R) F 127 und 0.9 % Kochsalz. Die mit einem modifizierten Cilas-Granulomter 2 Minuten nach der Herstellung ermittelte durchschnittliche Bläschengroße beträgt für 50 % < 45 µm.A 10% aqueous and sterile Pluronic (R) F 127 solution is removed with an injection syringe and injected with the highest possible outflow rate in 8 ml of a sterile physiological saline solution, which is in a sterile 25 ml multivial under an air atmosphere. The mixture is then shaken vigorously. The gas bubble suspension contains 2% Pluronic (R) F 127 and 0.9% table salt. The average bubble size determined with a modified Cilas granulometer 2 minutes after production is <45 µm for 50%.
Einer wäßrigen und sterilen 5 %igen Pluronic (R) F 68-Lösung, aus der vorher die gelöste Luft mit Argon verdrängt worden ist, werden 2 ml mit einer Injektionsspritze entnommen und mit möglichst hoher Ausströmungsgeschwindigkeit in 8 ml einer sterilen, wäßrigen 6 %igen Dextran 40-Lösung, aus der ebenfalls die geloste Luft mit Argon verdrängt worden ist und die sich in einem sterilen 25 ml Multivial unter ein Argon-Atmosphäre befinden, gespritzt Anschließend wird die Mischung stark geschüttelt. Die mit dem Cilas-Granulometer 715 2 Minuten nach der Herstellung ermittelte Größenverteilung der Argon-Gasblasen ergab für 50 % < 55 µm. Die erhaltene Gasblasensuspension enthält 1 % Pluronic (R) F 68 und 4.8 % Dextran 40.2 ml of an aqueous and sterile 5% Pluronic (R) F 68 solution, from which the dissolved air has previously been displaced with argon, are removed with an injection syringe and in 8 ml of a sterile, aqueous 6% solution with the highest possible outflow rate Dextran 40 solution, from which the dissolved air has also been displaced with argon and which are in a sterile 25 ml multivial under an argon atmosphere, is then injected. The mixture is then shaken vigorously. The size distribution of the argon gas bubbles, determined with the Cilas 715 granulometer 2 minutes after production, gave 50% <55 μm. The gas bubble suspension obtained contains 1% Pluronic (R) F 68 and 4.8% dextran 40.
Analog Beispiel 2, jedoch unter Verwendung von Helium anstelle von Argon, erhält man nach dem Mischvorgang eine Helium-Gasblasensuspension, die 1 % Pluronic (R) F 68 und 4.8 % Dextran 40 enthält.Analogously to Example 2, but using helium instead of argon, a helium gas bubble suspension is obtained after the mixing process, which contains 1% Pluronic (R) F 68 and 4.8% dextran 40.
Claims (5)
- Liquid composition for the uptake and stabilisation of gas bubbles filled with physiologically compatible gas for use as contrast medium in ultra sound diagnosis, consisting of a mixture ofa) from 0.01 to 10% by weight of one or more non-ionic surfactants from the group consisting of lecithins, lecithin fractions and derivatives thereof, polyoxyethylene fatty acid esters, polyoxyethylene fatty alcohol ethers, ethoxylated castor oils and hydrogenated derivatives thereof and polyoxyethylenepolyoxypropylene polymers, with water or with a physiologically compatible aqueous solution,
and of a mixture ofb) from 0.5 to 50% by weight of one or more viscosity-increasing substances from the group consisting of lactose, saccharose, polysaccharides, dextrans, cyclodextrins, hydroxyethyl starch, plasma proteins, gelatin, oxypolygelatin and other gelatin derivatives, and polyoxyethylenepolyoxypropylene polymers having a molecular weight of from 4 750 to 16 250, in water or in a physiologically compatible aqueous solution,
with the proviso that the total solution contains at least 0.01% by weight, preferably from 0.5 to 5% by weight, of the surfactant and at least 0.5% by weight of the viscosity-increasing substance, and with the further proviso that when there is used as surfactant a polyoxyethylenepolyoxypropylene polymer having a molecular weight of from 4 750 to 16 250 that simultaneously has a viscosity-increasing effect, the concentration thereof in the total solution is from 1 to 10%, preferably from 3 to 10%. - Liquid composition according to claim 1, characterised in that as surfactant it contains a polyoxyethylenepolyoxypropylene polymer with a molecular weight of from 6 800 to 8 975 (Pluronic (R) F 68) or of 16 250 (Pluronic (R) F 108) or of 13 300 (Pluronic (R) F 127).
- Liquid composition according to claim 1, characterised in that as surfactant it contains polyoxyethylene fatty acid stearate.
- Liquid composition according to any one of claims 1 to 3, characterized in that it contains as physiologically compatible aqueous solution the aqueous solution of a univalent or polyvalent alcohol, physiological electrolyte solution, infusion solution, or mixtures thereof.
- Liquid composition according to any one of claims 1 to 4, for the uptake and stabilization of gas bubbles filled with sterile air, carbon dioxide, oxygen, nitrogen, a noble gas, or mixtures thereof.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
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AT82730129T ATE18356T1 (en) | 1981-10-16 | 1982-10-13 | LIQUID MIXTURE FOR ABSORBING AND STABILIZING GAS BUBBLES FOR USE AS CONTRAST AGENT FOR ULTRASOUND DIAGNOSTICS AND ITS PRODUCTION. |
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DE3141641 | 1981-10-16 | ||
DE19813141641 DE3141641A1 (en) | 1981-10-16 | 1981-10-16 | ULTRASONIC CONTRAST AGENTS AND THEIR PRODUCTION |
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EP0077752A3 EP0077752A3 (en) | 1983-11-30 |
EP0077752B1 EP0077752B1 (en) | 1986-03-05 |
EP0077752B2 true EP0077752B2 (en) | 1995-07-26 |
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EP82730129A Expired - Lifetime EP0077752B2 (en) | 1981-10-16 | 1982-10-13 | Liquid mixture for absorbing and stabilizing gas bubbles to be used as contrast agent in ultrasonic diagnosis and process for its preparation |
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US (1) | US4466442A (en) |
EP (1) | EP0077752B2 (en) |
JP (1) | JPS5879930A (en) |
AT (1) | ATE18356T1 (en) |
AU (1) | AU558152B2 (en) |
CA (1) | CA1199577A (en) |
DE (2) | DE3141641A1 (en) |
DK (1) | DK160741C (en) |
FI (1) | FI81008C (en) |
IE (1) | IE55051B1 (en) |
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Also Published As
Publication number | Publication date |
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FI823474L (en) | 1983-04-17 |
DK160741C (en) | 1996-11-04 |
AU558152B2 (en) | 1987-01-22 |
DK160741B (en) | 1991-04-15 |
FI823474A0 (en) | 1982-10-12 |
EP0077752B1 (en) | 1986-03-05 |
NZ202186A (en) | 1986-07-11 |
ATE18356T1 (en) | 1986-03-15 |
EP0077752A2 (en) | 1983-04-27 |
IE822490L (en) | 1983-04-16 |
JPS5879930A (en) | 1983-05-13 |
CA1199577A (en) | 1986-01-21 |
JPH0443889B2 (en) | 1992-07-20 |
EP0077752A3 (en) | 1983-11-30 |
FI81008B (en) | 1990-05-31 |
DE3269667D1 (en) | 1986-04-10 |
DK455782A (en) | 1983-04-17 |
IE55051B1 (en) | 1990-05-09 |
NO158328B (en) | 1988-05-16 |
FI81008C (en) | 1996-06-28 |
ZA827577B (en) | 1983-08-31 |
DE3141641A1 (en) | 1983-04-28 |
NO823452L (en) | 1983-04-18 |
NO158328C (en) | 1988-08-24 |
AU8916382A (en) | 1983-04-21 |
US4466442A (en) | 1984-08-21 |
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